Isoindolo(2,1-d)(1,4)benzodiazepin-6,9(7h,13bh)diones



United States Patent 3,506,647 ISOINDOLO[2,1-d][1,4]BENZODIAZEPIN-6,9(7H,13bH)DIONES Goetz E. Hardtmann, Florham Park, and Hans Ott,Convent Station, N.J., assignors to Sandoz-Wander, Inc., a 5 corporationof Delaware No Drawing. Filed Apr. 14, 1967, Ser. No. 630,835

Int. Cl. C07d. 53/06, 27/06; A61k 27/00 US. Cl. 260-2393 2 ClaimsABSTRACT OF THE DISCLOSURE The compounds of this invention areisoindolo[2,1-d]

[1,4]benzodiazepin-6,9(7H,13bH)diones of the formula:

wherein R is a member selected from the group consisting of a hydrogenatom, and halo having an atomic weight of 19 to 80, i.e., fluoro,chloro, and bromo; and

R is alkyl having from 1 to 2 carbon atoms, i.e., methyl or ethyl.

Compounds I are obtainable by the procedure of the following reactionscheme wherein R and R are as defined above, X is halo of atomic weightof to 127, i.e., chloro, bromo and iodo, and R is lower alkyl, e.g.,methyl, ethyl, propyl, butyl, amyl or hexyl:

(1) Alkali metal base CH2COOR IV E U0 N cyclization Step b O Accordingto the reaction scheme Step a involves N- alkylating a compound II,i.e., a 3-(2-methylor .Z-ethyl- 3,506,647 Patented Apr. 14, 1970aminophenyl)isoindolin-l-one, with a compound III, i.e., a lower alkylester of an alpha-halo acetate, e.g. ethyl bromoacetate to form thecorresponding compound IV. The N-alkylation is effected in aconventional manner by (1) first forming an alkali metal salt of thecompound II and then (2) reacting said salt with compound III to obtainthe corresponding compound IV. It is preferred to (1) form an alkalimetal salt of the compound II by reacting the compound II with astrongly basic alkali metal-containing compound, e.g., NaH, underanhydrous conditions in a suitable solvent, e.g., N,N-dimethylformamideor N,N-dimethylacetamide, and then (2) react said salt of the compoundII under anhydrous conditions in a suitable solvent with a compound III,e.g., in situ, i.e., carrying out parts (1) and (2) sequentially byadding the compound III to the reaction mixture containing said salt ofcompound II. While the temperatures at which parts (1) and (2) arecarried out are not critical, temperatures of 40 to are preferred.

In Step b compound IV is cyclized to the corresponding compound I underacid conditions by conventional means. The cyclization is' preferablyeffected by dissolving the compound IV in a lower fatty acid, e.g.,glacial acetic acid or propionic acid (at least 100 parts by volume per15 parts of compound 1V), and then boiling off most, e.g., up to of thefatty acid, e.g., at atmospheric pressure.

Compounds II are obtainable by the procedures described in NetherlandsPatent 6,607,814, published Dec. 12, 1966.

Compounds I are useful as anticonvulsants, sedatives and tranquilizers.They are administered to mammals either orally or parenterally in dailydoses of from 1 to 5 mg./-kg. of body weight, e.g., for most mammalsfrom 60 to 300 milligrams per diem, preferably administered in doses of15 to 150 milligrams; a single daily oral dose is also acceptable.

Each of the pharmaceutically active compounds of this invention may be,e.g., incorporated for oral administration, in a tablet as the soleactive ingredient. A typical tablet is constituted by from 1 to 3percent binder, e.g., tragacanth; from 3 to 10 percent disintegratingagent, e.g., corn starch; from 2 to 10 percent lubricant, e.g., talcum;from 0.25 to 1.0 percent lubricant, e.g., magnesium stearate; andaverage dosage of active ingredient; and q.s. percent of filler, e.g.,lactose; all percentages being by weight. Tablets are prepared accordingto standard tabletting techniques, which are well-known in the art,employing the necessary amounts of conventional granulating liquids,e.g., alcohol SD30 and purified water. An exemplary tablettingformulation for the instant active compounds is:

An example illustrative of this invention follows. Throughout thisdisclosure all temperatures are centigrade (room temperature is 20) andall percents and parts are by weight, unless specified otherwise. Partsby weight are related to parts by volume as a kilogram is related to aliter.

3 EXAMPLE 2-chloro-S-methyl-isoindolo [2,1-d] [1,4]benzodiazepine- 6,9(7H, 13bH) dione N-CHa This example illustrates the preparation of acompound I according to the reaction scheme present above.

(a) 3- (5-chloro-2-methylaminophenyl -1-oxo-isoindolo- 2-acetic acidethyl ester Dissolve 16.2 parts of 3-(5-chloro-2-methylaminophenyl)isoindolin-l-one in 180 parts by volume of anhydrousN,N-dimethylformamide and add 2.5 parts of sodium hydride (as a 56%suspension in mineral oil). Warm the mixture to 60; add with stirring7.2 parts by volume of ethyl bromoacetate and maintain the mixture, withstirring, at 60 for 12 hours. Pour the reaction mixture over 500 partsof ice and extract thrice with 150 parts by volume portions ofchloroform. Wash the combined extracts with 150 parts by volume ofwater, then with 150 parts by volume of saturated aqueous sodiumchloride, and then dry over sodium sulfate. Remove the chloroform byevaporation under vacuum to obtain a residue, then add diethyl ether toprecipitate the crude compound (a). Recover the crude compound (a) byfiltration, then take up in chloroform and filter through silica gel toclarify. Recrystallize from ethanol to obtain purified compound (a)melting point, (M.P.) 149 to 153.

(b) 2-chloro-5-methyl-isoindolo [2,1-d] [1,4] benzodiazepine-6,9(7H,13bH)dione Dissolve 3 parts of compound (a), i.e., 3-(5-chloro-2-methylaminophenyl) 1 oxo isoindolo 2 acetic acid ethyl ester, in 60parts by volume of glacial acetic acid. Slowly distill off, atatmospheric pressure, 70% of the glacial acetic acid over a period of 8hours then remove the remainder of the glacial acetic acid under vacuumto obtain a residue. Dissolve the residue in 100 parts by volume ofmethylene chloride. Wash the solution with 50 parts by volume of 10%aqueous sodium carbonate, then wash with 50 parts by volume of water anddry over sodium sulfate. Concentrate the solution by evaporating undervacuum to 20 parts by volume and precipitate by addition of diethylether to obtain the title compound, M.P. 257 to 258 (starts to decomposeat 240 vBy following the procedure described in Step (2.) of thisexample but replacing the3-(S-chloro-Z-methylaminophenyl)isoindolin-1-one, i.e., a compound 11wherein R is chloro and R is methyl, with an equivalent of 3-(2-ethylaminophenyl)isoindolin-l-one, i.e., a compound II wherein R is ahydrogen atom and R is ethyl, results in a similar manner in thepreparation of the corresponding compound IV, i.e.,3-(2-aminoethylphenyl)-1-oxo-isoindolo-2-acetic acid ethyl ester, whichfollowing the procedure described in Step (b) of this example results inthe preparation of the corresponding compound I, i.e., 5-ethylisoindolo[2,1 d] [1,4] benzodiazepin 6,9(7H,l3bH) dione.

Each compound I has an asymmetric carbon atom (13b) and thus exists as aracemate or in an optically active form. Each of the optical antipodes(enantiomers) is within the scope of this invention. To obtain aparticular optical antipode of a compound I, an appropriate racemiccompound IV is converted from its ester form to its acid form (racemic),i.e., wherein R is a hydrogen atom, and resolution of said acid form iseifected according to wellknown procedures to obtain the desiredantipode, which is then converted to its ester form (antipode), i.e.,the corresponding compound IV, which is then converted by Step (b) tothe corresponding compound I (antipode). In some cases greaterpharmacological activity or other beneficial attribute may be found withrespect to a particular antipode, and in such instances administrationof such antipode may be preferred.

What is claimed is:

1. A compound of the formula wherein R is a member selected from thegroup consisting of a hydrogen atom, and halo having an atomic weight of19 to and R is alkyl having from 1 to 2 carbon atoms.

2. The compound according to claim 1 wherein R is chloro and R ismethyl.

References Cited UNITED STATES PATENTS 3,375,246 3/1968 Hardtmann et al.260239.3

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl.X.R.

